By Rick Weiss
Washington Post Staff Writer
Monday, April 25, 2005
Injections of genetically altered cells into the brain appear to nourish ailing neurons and may slow the cognitive decline in patients with Alzheimer's disease, scientists reported yesterday in a preliminary study.
The experimental approach, pursued by researchers at the University of California at San Diego, aims to rejuvenate brain cells by providing a steady supply of a nerve-nurturing hormone secreted by the injected cells.
In studies involving a half-dozen Alzheimer's patients, most showed evidence of increased nerve growth and activity in the region of the brain most affected by the degenerative disease. Psychological test scores suggested the treatment also tempered the slow slide into dementia that is characteristic of Alzheimer's.
"If these effects are borne out in larger, controlled trials, this could be a significant advance over existing therapies for Alzheimer's disease," said study leader Mark Tuszynski, director of UCSD's Center for Neural Repair and a neurologist at the San Diego Veterans Affairs Medical Center.
But Tuszynski and other experts cautioned that the study was designed to test the technique's safety, not its efficacy, so the hints of improvement -- while tantalizing -- are unreliable. And although the results do offer new evidence that nerve growth hormones may prove useful, the surgical implantation of gene-altered cells is widely considered to be too complicated a technique for the routine delivery of those hormones.
"This would not be a practical way of going around treating 4 1/2 or 5 million Alzheimer's patients, although it would be a boon for neurosurgeons," said Zaven Khachaturian, a science adviser to the Alzheimer's Association in Chicago and former director of the Office of Alzheimer's Research at the National Institutes of Health. For that reason, a simpler system of getting the hormones into the brain is being tested.
The experiments are the culmination of decades of research involving nerve growth factors, which encourage nerve cells to grow new branch-like projections that enhance communication with surrounding nerve cells.
Alzheimer's disease involves many kinds of changes in the brain, among them a loss of "cholinergic" neurons. Animal studies have shown that the prototypical nerve growth factor -- the one that bears the formal name Nerve Growth Factor or NGF -- can rejuvenate dying cholinergic neurons. So it has long been a goal of scientists to test NGF's usefulness in patients with the disease, which today has no cure.
Delivery has been the bottleneck. NGF is too big a molecule to get into the brain via the bloodstream. And when researchers injected the hormone directly into patients' brains a few years ago, it caused intolerable side effects, including intense pain.
In the new experiment, the San Diego team took skin cells from patients and enhanced them with snippets of DNA that gave the cells the ability to secrete NGF. Then, with the patients sedated but awake, the researchers injected the cells deep into their brains. The hope was that more gradual, sustained delivery of the hormone would provide benefits without side effects.
There were serious problems at first. Two patients moved abruptly while doctors were injecting the cells, resulting in brain damage and bleeding. One died a few weeks later from complications, and the other has suffered lingering problems that may be related to the surgery. That prompted a change so that all subsequent patients were treated under general anesthesia.
In the six other volunteers, the cells seem to have caused no problems. Perhaps most exciting, Tuszynski said, is evidence that the hormones have stimulated new outgrowths from cholinergic neurons. "This is the first direct evidence in human brains that a degenerating neuron will respond to a growth factor with new growth," said Tuszynski, who has a financial stake in a company, Seragen Pharmaceuticals of San Diego, that is investing in follow-up human studies.
Brain scans also showed that the treated areas were more metabolically active than before the treatment -- the opposite of what typically happens as Alzheimer's progresses. And two measures of mental status suggested a 50 percent slowing of the rate of decline in mental function over two years, the team reported in the journal Nature Medicine.
Those last results must be taken with big grains of salt, Tuszynski and others said, because patients often score better on tests when they and their doctors know they have received a novel treatment. Only more advanced studies, in which patients do not know whether they got a real treatment or not, will settle that question for NGF and Alzheimer's.
A previous study of a different nerve growth factor for Parkinson's disease looked even more promising in similar initial studies but proved useless in controlled follow-up studies, University of Colorado neurologist Curt Freed noted.
But even a modest delay in decline could have a big impact, said Marcelle Morrison-Bogorad, associate director of the Neuroscience and Neuropsychology of Aging Program at the National Institute on Aging. "Alzheimer's is a disease of old age, so even putting it off five or 10 years will really reduce the numbers of patients," she said, because many will die of other causes before the disease takes hold.
While the brain injections may seem radical, so is the disease, said Lennart Mucke, director of the Gladstone Institute of Neurological Disease at the University of California at San Francisco: "I think it is important to explore heroic approaches for Alzheimer's because it is obviously a devastating condition and the available treatments are of very limited benefit."
David A. Bennett, director of the Rush University's Alzheimer's Disease Center in Chicago, is leading an effort to deliver NGF more efficiently by injecting into patients' brains billions of genetically engineered viruses designed to make nerve cells produce the hormone on their own.
Four patients have been treated without complications, Bennett said.